Reduced presynaptic cholinergic function in the central nervous system contributes to the normal process of aging, as well as to the neuropathology observed in senile dementia of the Alzeheimer type (SDAT). Central muscarinic receptors appear to diminish with aging in both normal and pathological states, although not to the marked extent that the acetylcholine-synthesizing enzyme (CAT) is reduced. Currently, clinical investigations are examining therapeutic approaches to supplement the declining cholinergic function through the administration of cholinergic precursors and cholinomimetics, with variable success. Recent studies in animals have demonstrated the presence of subtypes of muscarinic receptors in the central nervous system. Further characterization of these subpopulations of muscarinic receptors, coupled with the development of selective agonists and antagonists, will permit a more detailed examination of the precise receptor loss taking place during aging and SDAT. Moreover, these studies will directly support the eventual development of selective cholinergic agonists to be used in the treatment of individuals suffering from this disease. This proposal initiates an investigation to characterize a broad spectrum of cholinergic antagonists for their abilities to differentiate muscarinic receptor subtypes. Once this has been accompished, these antagonists will be utilized in a neurally derived intact cell system (NG 108-15) which is known to possess muscarinic receptors and responses, to determine which muscarinic receptor subtype(s) is coupled to the adenylate cyclase response. The techniques to be used in studies of receptor binding and adenylate cyclase activity are well established in this laboratory. Extensions of these initial studies will provide an eventual characterization of the coupling of several cholinergically-linked responses (PI, cGMP, calcium), in these same cells, to respective muscarinic receptor subtypes. These studies will lead to a detailed examination of the biochemical and pharmacological characteristics of the loss of muscarinic function during aging, and particularly in SDAT. Ultrimately, this knowledge will foster the development of newer and safer approaches to the enhancement of cognitive performance in the elderly, and to treating SDAT.